4 Desferrioxamine-induced iron excretion in humans

Pippard, Martin J.

doi:10.1016/s0950-3536(89)80020-4

Cited by 56 publications

(50 citation statements)

References 75 publications

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“…Increasing doses of DFO (from 1 to 4 g) were given by 12-hour subcutaneous infusion on successive days with 24-hour collection of urine from the beginning of each infusion. 21 In patient 7 iron excretion was only measured after 2 g DFO, and in patient 8 not after 4 g. The iron excretion was determined by atomic absorption spectrophotometry. 22 Follow-up values represent means of three 24-hour collections performed on 3 successive days.…”

Section: Measurement Of Urinary Iron Excretionmentioning

confidence: 99%

Evaluation of myocardial iron by magnetic resonance imaging during iron chelation therapy with deferrioxamine: indication of close relation between myocardial iron content and chelatable iron pool

Jensen

Christensen

et al. 2003

Blood

159

129

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Evaluation of myocardial iron during iron chelation therapy is not feasible by repeated endomyocardial biopsies owing to the heterogeneity of iron distribution and the risk of complications. Recently, we described a noninvasive method based on magnetic resonance imaging. Here, the method was used for repeated estimation of the myocardial iron content during iron chelation with deferrioxamine in 14 adult nonthalassemic patients with transfusional iron overload. We investigated the repeatability of the method and the relationship between the myocardial iron estimates and iron status. The repeatability coefficient (2s D ) was 2.8 mol/g in the controls (day-to-day) and 4.0 mol/g in the patients (within-day). Myocardial iron estimates were elevated in 10 of all 14 patients at first examination, but normalized in 6 patients after 6 to 18 months of treatment. If liver iron declined below 350 mol/g all but one of the myocardial iron estimates were normal or nearly normal. At start (R 2 ‫؍‬ 0.69, P ‫؍‬ .0014) and still after 6 months of iron chelation (R 2 ‫؍‬ 0.76, P ‫؍‬ .001), the estimates were significantly and more closely related to the urinary iron excretion than to liver iron or serum ferritin levels. In conclusion, our preliminary data, which may only pertain to patients with acquired anemias, suggest the existence of a critical liver iron concentration, above which elevated myocardial iron is present, but its extent seems related to the size of the chelatable iron pool, as reflected by the urinary iron excretion. This further supports the concept of the labile iron pool as the compartment directly involved in transfusional iron toxicity. (Blood. 2003;101:4632-4639)

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Section: Measurement Of Urinary Iron Excretionmentioning

confidence: 99%

Evaluation of myocardial iron by magnetic resonance imaging during iron chelation therapy with deferrioxamine: indication of close relation between myocardial iron content and chelatable iron pool

Jensen

Christensen

et al. 2003

Blood

159

129

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“…[3,4] However, DFO suffers from the disadvantage that it is not orally active and is rapidly cleared by the kidneys. [5,6] Therefore, there is an urgent need to develop an ironA C H T U N G T R E N N U N G (III)-selective, orally active and non-toxic sequestering agent. 3-Hydroxypyridin-4-ones (HPOs) are currently one of the main candidates for the development of such chelators.…”

Section: Introductionmentioning

confidence: 99%

Amido‐3‐hydroxypyridin‐4‐ones as Iron(III) Ligands

Piyamongkol

Yong

Kong

et al. 2010

Chemistry A European J

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The synthesis and physicochemical properties of a range of 2- and 6-amido-3-hydroxypyridin-4-ones are described. All the amido-substituted 3-hydroxypyridin-4-ones have lower pK(a) values than 1,2-dimethyl-3-hydroxypyridin-4-one (deferiprone). This is due to the inductive effect of the amido group. Furthermore, the pK(a) values of the 3-hydroxy group in 1-nonsubstituted pyridinones are dramatically lower than those of the corresponding 1-alkyl analogues, indicating that a strong hydrogen bond exists between the 2-amido function and the 3-oxygen anion, which stabilises the anion. As a result of the decreased competition with protons, the pFe(3+) values of this group of molecules are higher than that of deferiprone. The distribution coefficients of these molecules are also increased despite the lack of a hydrophobic 1-alkyl substituent and this is ascribed to the intramolecular hydrogen bond. X-ray diffraction studies confirm the existence of the intramolecular hydrogen bond.

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“…DFO, a hexacoordinate hydroxamate iron chelator produced by Streptomyces pilosus ,41 is not orally active and is best administered sc by continuous infusion over long periods of time, 11,42 a patient compliance issue. 11,43 Deferiprone, an orally active bidentate chelator, is less efficient than sc DFO at removing iron.…”

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confidence: 99%

Design, Synthesis, and Testing of Non-Nephrotoxic Desazadesferrithiocin Polyether Analogues

Bergeron

Wiegand²,

McManis³

et al. 2008

J. Med. Chem.

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A series of iron-clearing efficiencies (ICEs), ferrokinetics, and toxicity studies for (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid (deferitrin, 1), (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (2) and (S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (3) are reported. The ICEs in rodents are shown to be dose-dependent and saturable for ligands 2 and 3 and superior to 1. Both polyether analogues in subcutaneous (sc) versus oral (po) administration in rodents and primates demonstrated excellent bioavailability. Finally, in a series of toxicity studies of ligands 1-3, the dosing regimen was shown to have a profound effect in animals treated with ligand 1. When ligand 1 was given at doses of 237 µmol/kg/day twice a day (b.i.d.), there was serious proximal tubule damage versus 474 µmol/kg/day once daily (s.i.d.). With 2 and 3, in iron-overloaded and/or non-iron-loaded rodents, kidney histopathologies remained normal.Although iron comprises 5% of the earth's crust, living systems have great difficulty in accessing and managing this vital micronutrient. The low solubility of Fe(III) hydroxide (K sp = 1 × 10 −39 ), 1 the predominant form of the metal in the biosphere, has led to the development of sophisticated iron storage and transport systems in nature. Microorganisms utilize low molecular weight, virtually ferric ion-specific ligands, siderophores 2-6 higher eukaryotes tend to employ proteins to transport and store iron (e.g., transferrin and ferritin, respectively). [7][8][9] Humans absorb and excrete only about 1 mg of the metal daily; there is no effective mechanism for the excretion of excess iron. 10 In humans, nontransferrin-bound plasma iron, a heterogeneous pool of the metal in the circulation, unmanaged iron, seems to be a principal source of iron-mediated organ damage. Introduction of excess iron into this closed system, whether derived from transfused red blood cells [11][12][13] or from increased absorption of dietary iron, 14,15 leads to a build up of the metal in the liver, heart, pancreas, and elsewhere. Such iron accumulation eventually produces (i) liver disease that may progress to cirrhosis, [16][17][18] (ii) diabetes related both to iron-induced decreases in pancreatic β-cell secretion 19,20 and increases in hepatic insulin resistance, and (iii) heart disease, still the leading cause of death in thalassemia major [21][22][23] and related forms of transfusional iron overload.The toxicity associated with excess iron, whether a systemic or a focal problem, derives from its interaction with reactive oxygen species, for instance, endogenous hydrogen peroxide (H 2 O 2 ). [24][25][26][27] In the presence of Fe(II), H 2 O 2 is reduced to the hydroxyl radical (HO • ), a very reactive species, and HO − , a process known as the Fenton reaction. The Fe(III) liberated can NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript be reduced back to Fe(II) via ...

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4 Desferrioxamine-induced iron excretion in humans

Cited by 56 publications

References 75 publications

Evaluation of myocardial iron by magnetic resonance imaging during iron chelation therapy with deferrioxamine: indication of close relation between myocardial iron content and chelatable iron pool

Evaluation of myocardial iron by magnetic resonance imaging during iron chelation therapy with deferrioxamine: indication of close relation between myocardial iron content and chelatable iron pool

Amido‐3‐hydroxypyridin‐4‐ones as Iron(III) Ligands

Design, Synthesis, and Testing of Non-Nephrotoxic Desazadesferrithiocin Polyether Analogues

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